Hemofilter for in vivo blood filtration

ABSTRACT

Hemofilters for in vivo filtration of blood are disclosed. The hemofilters disclosed herein provide an optimal flow of blood through the filtration channels while maintaining a pressure gradient across the filtration channel walls to enhance filtration and minimize turbulence and stagnation of blood in the hemofilter.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional PatentApplication No. 62/523,131, filed Jun. 21, 2017, which application isincorporated herein by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under grant no. U01EB021214 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

INTRODUCTION

End Stage Renal Disease (ESRD) remains a major public health problem inthe United States, afflicting over 615,000 people with nearly 116,000new patients initiating treatment each year. Due to the shortfall inorgan availability, the majority of ESRD patients in the United Statesundergo in-center, 3-4 hour, thrice weekly dialysis, such ashemodialysis or peritoneal dialysis.

Hemodialysis involves passing a patient's blood against a synthetic orsemisynthetic membrane and inducing diffusive transport of toxins fromthe blood into a bath of dialysate on the other side of the membrane. Inperitoneal dialysis, the patient's parietal peritoneal epitheliumperforms the function of the dialysis membrane.

SUMMARY

A hemofilter for use in for filtering blood in vivo, the hemofilter isprovided. In certain embodiments, the hemofilter includes an extendedinlet manifold; a plurality of filtration channels; and an extendedoutlet manifold, the extended inlet manifold comprising a first regioncomprising a circular inlet configured for connection to a blood vesselof an individual; and a transition section in which lumen of theextended inlet manifold transitions from having a circular cross-sectionto having a substantially rectangular cross-section; and a second regioncomprising a U-shaped turn and followed by a linear tapered section, thelinear tapered section comprising a plurality of openings in fluidcommunication with the plurality of filtration channels, wherein theplurality of filtration channels are arranged in a spaced-apart stackedconfiguration and are in fluid communication with a plurality ofopenings in a first region of the outlet manifold, wherein the firstregion of the outlet manifold is parallel to the linear tapered sectionof the extended inlet manifold and is reverse-tapered and wherein theoutlet manifold comprises a second region comprising a transitionsection in which lumen of the outlet manifold transitions from having arectangular cross-section to having a circular cross-section; and acircular outlet defined by the circular cross-section of the outletmanifold, and wherein the hemofilter is configured for entry of bloodthrough the inlet and for transporting the blood through the transitionsection of the extended inlet manifold to the tapered linear section,into the plurality of filtration channels to the first region of theoutlet manifold, into the transition section of the outlet manifold, andexit via the circular outlet.

In certain embodiments, the plurality of filtration channels aresubstantially rectangular (e.g., with a length longer than width andsubstantially rounded corners) and are stacked in a parallelconfiguration.

In certain embodiments, the transition section in extended inletmanifold includes a turn which changes direction of blood flow withreference to the direction in the inlet by 60°-120°.

In certain embodiments, the U-shaped turn in the second region of theextended inlet manifold changes the direction of blood flow withreference to the direction in the transition section by 150° and 210°.

In certain embodiments, the tapered section of the extended inletmanifold decreases in height. In certain embodiments, the taperedsection of the extended inlet manifold decreases in width.

In certain embodiments, the plurality of filtration channels comprises2-50 channels, e.g., 6-30 channels.

In certain embodiments, the plurality of filtration channels comprises afirst curved region connected to the tapered section of the extendedinlet manifold, a linear section, and a second curved region connectedto the reverse-tapered section of the outlet manifold, wherein thecurvature of the first curved region is opposite to the curvature of thesecond curved region.

In certain embodiments, the plurality of channels each define arectangular channel lumen enclosed by a top surface, a bottom surface,and side walls connecting the top and bottom surfaces.

In certain embodiments, the top surface comprises a membrane forfiltration of blood in the channel lumen. In certain embodiments, thebottom surface comprises a membrane for filtration of blood in thechannel lumen.

In certain embodiments, the tapered section of the extended inletmanifold and the reverse-tapered section of the outlet manifold and atop channel of the plurality of channels and a bottom channel of theplurality of channels are arranged in shape of a parallelogram. In someembodiments, the acute angles of the parallelogram shape defined by theconfiguration of the hemofilter may range from 75-25 degree, such as,70-30 degree, 65-30 degree, 65-35 degree, or 50-40 degree and the obtuseangles of the parallelogram shape defined by the configuration of thehemofilter may range from 105-155 degree, such as, 110-150 degree,115-150 degree, 115-145 degree, or 130-140 degree, respectively.

In certain embodiments, the plurality of channels are shaped anddimensioned to provide a volumetric flow rate of 20-100 ml/min, e.g.,25-100 ml/min for blood flowing through each of the channels and whereinthe hemofilter provides a volumetric flow rate of 750-2000 ml/min forblood flowing through the hemofilter.

In certain embodiments, each of the plurality of channels has a lengthof 10 mm-200 mm, e.g., 40 mm-100 mm. In certain embodiments, each of theplurality of channels has a width of 5 mm-100 mm, e.g., 10 mm-40 mm. Incertain embodiments, each of the plurality of channels has a height of0.5 mm-2.5 mm.

Also provided herein is a hemofilter for use in filtering blood in vivo,the hemofilter comprising: an extended inlet conduit; a singleserpentine filtration channel; and an outlet conduit; the extended inletconduit comprising: a first region comprising: an inlet having acircular cross section geometry configured for connection to a bloodvessel of an individual; and a transition region in which lumen enclosedby the first region transitions from the circular cross section shapeinto a rectangular cross section shape; a second region comprising arectangular cross section and a curved region connected to theserpentine filtration channel; the serpentine filtration channelcomprising: a plurality of filtration sections arranged in aspaced-apart stacked configuration wherein the plurality of filtrationsections are connected via turnaround sections; and the outletcomprising: first region having a rectangular cross-section; and asecond region that transitions from rectangular to a circular crosssection and terminates in a circular outlet configured for connection toa blood vessel of the individual.

Also provided herein is a hemofilter that includes an extended inletconduit; a single serpentine filtration channel; and an outlet conduit;the extended inlet conduit comprising: an inlet; a first transitionregion; a first turnaround section; a second transition region; a secondturnaround section; wherein in the first transition region the inlettransitions from a circular cross section, configured for connection toa blood vessel of an individual, into a substantially rectangular crosssection, wherein the rectangular cross section at the end of the firsttransition region matches the rectangular cross section of the firstturnaround section, wherein in the second transition region the firstturnaround section expands in width such that the rectangular crosssection at the end of the second transition region matches therectangular cross section of the second turnaround section, wherein therectangular cross section of the second turnaround section matches thatof the serpentine filtration channel; the serpentine filtration channelcomprising a plurality of filtration sections arranged in a spaced-apartstacked configuration wherein the plurality of filtration sections areconnected via turnaround sections; and the outlet comprising firstregion having a rectangular cross-section; and a second region thattransitions from rectangular to a circular cross section and terminatesin a circular outlet configured for connection to a blood vessel of anindividual.

In certain embodiments, the plurality of filtration sections comprise2-50 filtration sections, e.g., 6-30 filtration sections, each disposedbetween two turnaround sections.

In certain embodiments, the plurality of filtration sections each definea rectangular lumen enclosed by a top surface, a bottom surface, andside walls connecting the top and bottom surfaces.

In certain embodiments, the top surface comprises a membrane forfiltration of blood in the channel lumen. In certain embodiments, thebottom surface comprises a membrane for filtration of blood in thechannel lumen.

In certain embodiments, the plurality of filtration sections are shapedand dimensioned to provide a volumetric flow rate of 20-100 ml/min forblood flowing through the each of the filtration sections and whereinthe hemofilter provides a volumetric flow rate of 750-2000 ml/min forblood flowing through the hemofilter.

In certain embodiments, each of the plurality of filtration sections hasa length of 10 mm-200 mm, e.g., 40 mm-100 mm. In certain embodiments,each of the plurality of filtration sections has a width of 5 mm-100 mm,e.g., 10 mm-40 mm. In certain embodiments, each of the plurality offiltration sections has a height of 0.5 mm-2.5 mm.

In certain embodiments, the curvature of the turnaround sections isnon-uniform.

In certain embodiments, the curvature of the turnaround sections iscircular.

In certain embodiments, the curvature of the turnaround sections iselliptical.

In certain embodiments, the height of a filtration section increasesfrom a proximal end, at which blood enter the filtration section,towards the distal end, at which blood exits the filtration section andflows to a turnaround section.

The hemofilter may be used for filtering blood in vivo in a subject inneed thereof. In certain embodiments, the subject may have a reducedrenal function. The hemofilter provided herein may be incorporated in animplantable artificial kidney for filtering the subject's blood in vivo.The artificial kidney may replace or supplement dialysis treatment forthe subject.

In certain embodiments, the subject may have reduced heart function,such as, congestive heart failure (CHF). The hemofilter provided hereinmay be incorporated in a filtration device implanted into the subjectfor filtration of blood in order to unload blood volume accumulated dueto the reduced heart function, such as, CHF.

In certain embodiments, the subject may have reduced liver function,such as, liver failure. The hemofilter provided herein may beincorporated in a filtration device implanted into the subject forfiltration of blood in order to filter blood in the subject havingreduced liver function, such as, liver failure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an embodiment of a hemofilter as disclosed herein.

FIG. 2 provides a side view of the extended inlet of the hemofilterdepicted in FIG. 1.

FIG. 3 provides a side view of an embodiment of a hemofilter showing aninlet manifold with a tapering width.

FIG. 4 depicts another embodiment of a hemofilter as disclosed herein.

FIGS. 5A and 5B depict another embodiment of an inlet manifold of ahemofilter.

FIG. 6 shows a schematic of a hemofilter with an inlet manifoldconnected with multiple substantially parallel conduits.

FIGS. 7A and 7B depict an embodiment of a hemofilter inlet manifold.

FIG. 8 provides different angle views of a hemofilter with an inletmanifold connected with multiple substantially parallel conduits.

FIG. 9 shows a schematic of hemofilter with multiple substantiallyparallel conduits connected to an outlet manifold.

FIG. 10 provides a hemofilter with an outlet manifold connected withmultiple substantially parallel conduits (connected to an inletmanifold).

FIG. 11 illustrates an embodiment of a hemofilter as disclosed herein.

FIG. 12 illustrates an embodiment of a hemofilter as disclosed herein.

FIG. 13 illustrates an embodiment of a hemofilter as disclosed herein.

FIG. 14 provides a different view of the hemofilter depicted FIG. 13.

FIG. 15 illustrates the speed contours of blood on an XY-symmetry plane,showing a smooth transition from inlet to the inlet manifold to multipleconduits to outlet manifold and to outlet of a hemofilter.

FIG. 16 provides a zoomed in image of FIG. 15.

FIG. 17 provides an illustration of the flow velocity in the multipleconduits/channels.

FIG. 18 provides a bar graph of a hemofilter of FIG. 17, showing flowrate (ml/min) variation in each channel.

FIG. 19 provides an illustration of the static pressure contours in ahemofilter provided herein.

FIG. 20 provides an illustration of the wall shear stress in ahemofilter described herein.

FIG. 21 provides an illustration of the wall shear stress at thetransition from inlet manifold to the parallel conduits in a hemofilter.

FIG. 22 provides an illustration of the blood velocity along anXY-symmetry plane and wall shear stress in a hemofilter device describedherein.

FIG. 23 provides an illustration of the platelet stress accumulation(PSA) along particle paths in a hemofilter device, where the highest PSAis present along the corners and near the walls in regions of thehemofilter where flow rate is lowest.

FIG. 24 provides an illustration of the hemofilter comprising an inletconduit, an outlet conduit, and serpentine flow channel between inletand outlet conduits.

FIG. 25 illustrates a hemofilter device with an extended serpentine flowchannel and an extended inlet.

FIG. 26 provides a zoomed in view of the inlet and serpentine channel ofFIG. 25.

FIG. 27 provides a zoomed in view of the serpentine channels of FIG. 25showing a contoured turnaround region 27.

FIG. 28 illustrates blood velocity on an XY-symmetry plane, showingsmooth flow patterns through the turnaround sections of the serpentineflow channel.

FIG. 29 illustrates a zoomed in view of contour for velocity of bloodthrough the serpentine channel of FIG. 28, showing a good transitionfrom the inlet to the serpentine channel with the range of 0.24-0.48m/sec, with smooth and repeatable flow patterns through the turnaroundsections.

FIG. 30 illustrates speed contours in the YZ plane, near the turnaroundregions of the serpentine channel with good uniformity and repeatabilityof flow amongst and within the serpentine channel.

FIG. 31 illustrates the static pressure contours in the XY centerlineplane of the hemofilter.

FIG. 32 illustrates regions of low wall shear stress in the hemofilter.

FIG. 33 illustrates platelet stress accumulation along particle paths ina hemofilter with serpentine channel, showing the highest PSA along thecorners and near the walls in the slowest moving regions of thechannels.

FIG. 34 illustrates channel flow path geometry of a hemofilter with aserpentine channel.

FIG. 35 illustrates an outer view of an ellipse shaped channel flow pathgeometry (ellipse 1) with wall shear stress contours.

FIG. 36 illustrates an inner view of an ellipse shaped channel flow pathgeometry (ellipse 1) with wall shear stress contours.

FIG. 37 illustrates another view of an ellipse shaped channel flow pathgeometry (ellipse 1) with wall shear stress contours.

FIG. 38 illustrates an ellipse shaped channel flow path geometry(ellipse 1) showing fluid velocity for blood flowing from top region tobottom region of a serpentine channel on XY symmetry plane.

FIG. 39 illustrates an ellipse shaped channel flow path geometry(ellipse 1) showing fluid velocity for blood flowing from bottom regionto top region of a serpentine channel on XY symmetry plane.

FIG. 40 illustrates an ellipse shaped channel flow path geometry(ellipse 1) showing velocity vectors for blood flowing from top regionto bottom region of a serpentine channel on XY symmetry plane.

FIG. 41 illustrates an ellipse shaped channel flow path geometry(ellipse 1) showing velocity vectors for blood flowing from bottomregion to top region of a serpentine channel on XY symmetry plane.

FIG. 42 illustrates an ellipse shaped channel flow path geometry(ellipse 2) showing wall shear stress contours for blood flowing fromtop region to bottom region of a serpentine channel on XY symmetryplane.

FIG. 43 illustrates an ellipse shaped channel flow path geometry(ellipse 2) showing wall shear stress for blood flowing from bottomregion to top region of a serpentine channel on XY symmetry plane.

FIG. 44 illustrates an ellipse shaped channel flow path geometry(ellipse 2) showing fluid velocity for blood flowing from top region tobottom region of a serpentine channel on XY symmetry plane.

FIG. 45 illustrates an ellipse shaped channel flow path geometry(ellipse 2) showing fluid velocity for blood flowing from bottom regionto top region of a serpentine channel on XY symmetry plane.

FIG. 46 illustrates an ellipse shaped channel flow path geometry(ellipse 2) showing velocity vectors for blood flowing from top regionto bottom region of a serpentine channel on XY symmetry plane.

FIG. 47 illustrates an ellipse shaped channel flow path geometry(ellipse 2) showing velocity vectors for blood flowing from bottomregion to top region of a serpentine channel on XY symmetry plane.

FIGS. 48 and 49 illustrate an ellipse shaped channel flow path geometry(ellipse 3) showing wall shear stress contours for blood flowing fromtop region to bottom region of a serpentine channel on XY symmetryplane.

FIG. 50 illustrates an ellipse shaped channel flow path geometry(ellipse 3) showing wall shear stress contours for blood flowing frombottom region to top region of a serpentine channel on XY symmetryplane.

FIG. 51 illustrates an ellipse shaped channel flow path geometry(ellipse 3) showing fluid velocity for blood flowing from top region tobottom region of a serpentine channel on XY symmetry plane.

FIG. 52 illustrates an ellipse shaped channel flow path geometry(ellipse 3) showing fluid velocity for blood flowing from bottom regionto top region of a serpentine channel on XY symmetry plane.

FIG. 53 illustrates an ellipse shaped channel flow path geometry(ellipse 3) showing velocity vectors for blood flowing from top regionto bottom region of a serpentine channel on XY symmetry plane.

FIG. 54 illustrates an ellipse shaped channel flow path geometry(ellipse 3) showing velocity vectors for blood flowing from bottomregion to top region of a serpentine channel on XY symmetry plane.

FIGS. 55 and 56 illustrate channel flow path geometries of a hemofilterprovided herein.

FIGS. 57 and 58 illustrate channel flow path geometries of a hemofilter.

FIG. 59 illustrates static pressure contours of a hemofilter withserpentine channel provided herein.

FIG. 60 illustrates symmetry plane velocity contours of a hemofilterwith serpentine channel provided herein.

FIG. 61 illustrates velocity contours in a serpentine channel with ahigher velocity at entrance of a section of the channel introduced dueto blood traversing through a turn.

FIG. 62 illustrates streamlines colored by velocity of a hemofilterprovided herein, where the flow fills the extended inlet.

FIGS. 63 and 64 illustrate velocity vectors at the mid plane of theextended inlet of the hemofilter.

FIG. 65 illustrates velocity vectors at the midplane of the outletconduit of the hemofilter. FIG. 65 shows a smooth flow into the outletconduit.

FIG. 66 illustrates wall shear stress contours of the hemofilter device,depicting a small region of higher wall shear stress where the inlettransitions from a circular cross section to a rectangular crosssection.

FIG. 67 illustrates wall shear stress contours of the hemofilter shownin FIG. 66.

FIG. 68 illustrates resident time on the XY symmetry plane of thehemofilter shown in FIG. 66, where the mass average resident time at theoutlet conduit is 9.04 seconds, whereas longer resident times occur forthe blood flow near the walls.

FIG. 69 illustrates accumulated stress on XY symmetry plane of thehemofilter, where accumulated stress is a time integral of viscosity Xstrain rate along the channel flow path.

FIG. 70 illustrates a hemofilter device that includes a serpentinechannel and a dialysate/conduit.

FIGS. 71 and 72 illustrate a hemofilter device that includes aserpentine channel and a ultrafiltrate conduit.

FIG. 73 illustrates a section of a serpentine channels and anultrafiltrate conduit of a hemofilter device provided herein.

FIG. 74 illustrates a hemofilter where different turnaround regionsconfigurations change flow direction by 150 to 210 degrees.

FIG. 75 illustrates regions of a serpentine channel of a hemofilterwhere the channel flow path shows varying geometric profiles (i.e.,circular, elliptical, parabolic).

FIGS. 76A and 76B provide an illustration of the hemofilter comprisingan extended inlet conduit with two turnaround sections, an outletconduit, and serpentine flow channel between inlet and outlet conduits.

FIG. 77 illustrates probability density function (pdf) and accumulatedstress as measured in hemofilters with Parallel configuration, AltSerpentine configuration, or Serpentine configuration.

FIG. 78 illustrates probability density function (pdf) and normalizedaccumulated stress as measured in hemofilters with Parallelconfiguration, Alt Serpentine configuration, or Serpentineconfiguration. Accumulated stress activation limit was set at 1.

DETAILED DESCRIPTION

Provided herein are hemofilters for use in an implantable filtrationdevice, e.g., artificial kidney for continuous filtration(ultrafiltration and/or dialysis) of blood in an individual. Thehemofilters disclosed herein provide an optimal flow of blood throughthe filtration channels while maintaining a pressure gradient across thefiltration channel walls to enhance filtration and minimize areas ofhigh shear and stagnation of blood in the hemofilter.

Before exemplary embodiments of the present invention are described, itis to be understood that this invention is not limited to particularembodiments described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present invention will be limited onlyby the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimits of that range is also specifically disclosed. Each smaller rangebetween any stated value or intervening value in a stated range and anyother stated or intervening value in that stated range is encompassedwithin the invention. The upper and lower limits of these smaller rangesmay independently be included or excluded in the range, and each rangewhere either, neither or both limits are included in the smaller rangesis also encompassed within the invention, subject to any specificallyexcluded limit in the stated range. Where the stated range includes oneor both of the limits, ranges excluding either or both of those includedlimits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, some potential andexemplary methods and materials may now be described. Any and allpublications mentioned herein are incorporated herein by reference todisclose and describe the methods and/or materials in connection withwhich the publications are cited. It is understood that the presentdisclosure supersedes any disclosure of an incorporated publication tothe extent there is a contradiction.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “amembrane” includes a plurality of such membranes and reference to “theparallel conduit” includes reference to one or more conduits, and soforth.

It is further noted that the claims may be drafted to exclude anyelement which may be optional. As such, this statement is intended toserve as antecedent basis for use of such exclusive terminology as“solely”, “only” and the like in connection with the recitation of claimelements, or the use of a “negative” limitation.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.To the extent such publications may set out definitions of a term thatconflicts with the explicit or implicit definition of the presentdisclosure, the definition of the present disclosure controls.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

Definitions

The term “about” or “substantially similar” as used herein whenreferring to a measurable value such as a physical quantity, a temporalduration, and the like, is meant to encompass variations of ±20%, suchas ±10%, such as ±5%, ±1%, including ±0.1% from the specified value, assuch variations are typical of measurements characterizing the discloseddevices or appropriate to perform the disclosed methods.

As used herein “substantially”, may be applied to modify anyquantitative representation that could permissibly vary withoutresulting in a change in the basic function to which it is related. Forexample, two silicon nanoporous membranes may be somewhat non-parallelto each other if the stackable structure of the membranes, and thehydrodynamic and/or filtration properties of the silicon nanoporousmembranes are not materially altered.

A “plurality” contains at least 2 members. In certain cases, a pluralitymay have at least 10, at least 20, at least 30, at least 100, at least10,000, or more members.

“Biocompatible,” as used herein, refers to a property of a material thatallows for prolonged contact with a tissue in a subject without causingtoxicity or significant damage.

“Planar” as used herein, may be applied to describe a three dimensionalshape of any object, where the length scale of two dimensions that aresubstantially perpendicular to each other (e.g., length and width) islonger than the length scale of a third dimension (e.g., thickness) thatis substantially perpendicular to both of the other two dimensions. Thelength scale of one of the two longer dimensions may be similar to ordifferent from the other longer dimension. The first two dimensions maydefine a plane.

“Through channel” or “through hole” is used herein to describe a channelor hole that connects one side of the structure in which the channel orhole is formed, to another side of the structure. The first side and thesecond side are generally opposite sides of the structure.

“Nanopore” as used herein, refers to a pore that penetrates a substratefrom one side to another, where the pore has at least one lateraldimension (e.g., width and/or length, but not the height/thickness ofthe pore across the substrate) that is in the nanometer range, e.g., inthe range of 1.0 nm to 1,000 nm.

“Pumpless” as used in reference to a device connected to a blood vesselor a blood circuit is meant to refer to the absence of a pump mechanismother than the heart that drives blood flow through the circulatorysystem of an individual.

As used herein, the term “individual” refers to any animal, such as amammal like a dog, cat, livestock (e.g., pig), non-human primate, andincluding a human. The individual may be a patient with a compromisedkidney function and/or in need of dialysis, compromised heart function,and/or compromised liver function.

As used herein, the term “filtration” as used herein refers to a processof separating smaller particulates and larger particulates present in afluid, by passing the fluid through or over a filtering material thatwill not pass particulates having a size larger than pores in thefilter. Filtration is also affected by flow rate of the fluid as well asconcentration and pressure gradient across the filter. The filter may bea semipermeable membrane.

As used herein, the term “dialysis” refers to a form of filtration, or aprocess of selective diffusion through a membrane; it is typically usedto separate low-molecular weight solutes that diffuse through themembrane from the colloidal and high-molecular weight solutes which donot. In some embodiments, a feed of fluid is passed over a semipermeablemembrane, and a feed of dialysate is passed over the other side of thatmembrane; the membrane is wetted by one or both fluids, and then thereis diffusive transport of solutes between the fluids. The composition ofone fluid, the dialysate, may be used to deplete the composition of theother fluid, the feed fluid, of some molecule or molecules.

As used herein, the term “ultrafiltration” refers to subjecting a fluidto filtration under pressure, where the filtered material is very small;typically, the fluid includes colloidal, dissolved solutes or very finesolid materials, and the filter is a microporous, nanoporous, or asemi-permeable medium. A typical medium is a membrane. The fluid to befiltered is referred to as the “feed fluid.” During ultrafiltration, thefeed fluid is separated into a “permeate” or “filtrate” or“ultrafiltrate,” which has been filtered through the filter, and a“retentate,” which is that part of the feed fluid which did not getfiltered through the medium, or which is retained within the membrane.Ultrafiltration does not require a dialysate be passed over the otherside of the membrane.

As used herein, the term “dialysate” is used to refer to the fluid intowhich low-molecular weight solutes diffuse through a membrane fromanother fluid (typically, the feed fluid) initially containing thesesolutes.

As used herein, the term “polysilicon” refers to a polycrystalline formof silicon that is deposited as a thin film. It is used inmicroelectronics for transistors and wiring. In MEMS, polysilicon isusually used as structural material for devices.

Hemofilters

Provided herein are hemofilters for use in an implantable filtrationdevice, e.g., an artificial kidney for continuation filtration of bloodin an individual. The hemofilters disclosed herein provide an optimalflow of blood through the hemofilter while maintaining a pressuregradient across the filtration channel walls to enhance filtration andminimize areas of high shear and stagnation of blood in the hemofilter.The hemofilters disclosed herein do not require a pump to flow bloodthrough the channels and can perform filtration (dialysis orultrafiltration) of blood under systolic blood pressure.

The hemofilters disclosed herein include an inlet conduit that connectsto the circulatory system of an individual to transport arterial bloodthrough channels that include filters (e.g., membranes through whichcertain molecules, such as, uremic toxins, excess ions, small solutes,water, etc. can pass) and an outlet conduit through which the filteredblood exits the hemofilter. The other chamber of the implantablefiltration device, such as, an artificial kidney may be a bioreactorchamber which may include cells that express or provide one or moredesired factors to a filtered blood that is to be returned to theindividual. Suitable bioreactor systems are described in, e.g., US20090131858, which is incorporated herein by reference.

In certain embodiments, the hemofilter may include an extended inletconduit that transitions from a circular cross section into rectangularcross section, where the circular cross section region connects to ablood vessel of an individual and the rectangular cross section connectsto one or more channels configured for filtration of blood. In certainembodiments, the hemofilter may also include an outlet conduit thattransitions from a rectangular cross section into a circular crosssection, where the rectangular cross section connects to the one or morechannels configured for filtration of blood and the circular crosssection connects to a blood vessel of the individual or to a bioreactorchamber of the in vivo filtration device, e.g., an artificial kidney,which returns the filtered blood to a blood vessel of the individual. Incertain embodiments, the extended inlet conduit is longer than theoutlet conduit and includes one or more turns to enable adjacentplacement of the circular cross section region of the extended inletconduit and outlet conduits. In one aspect, a hemofilter as providedherein may have an extended inlet conduit that connects to a singleserpentine filtration channel. In a second aspect, a hemofilter asprovided herein may have an extended inlet conduit that includes aplurality of openings connected to a plurality of filtration channels.An extended inlet conduit that includes a plurality of openings isreferred to herein as an extended inlet manifold. Hemofilters with anextended inlet manifold connected to a plurality of filtration channelsand hemofilters with an extended inlet conduit that connects to a singleserpentine filtration channel are described in detail below.

In certain embodiments, the tapered section of the extended inletmanifold and the reverse-tapered section of the outlet manifold and atop channel of the plurality of channels and a bottom channel of theplurality of channels are arranged in shape of a parallelogram.

Hemofilters with Extended Inlet Manifold

Embodiments of the implantable filtration device, such as, abioartificial kidney, include a hemofilter with an extended inletmanifold that distributes blood into a plurality of filtration channels.The plurality of filtration channels is in fluid communication with anoutlet manifold which connects to a bioreactor chamber of the in vivofiltration device, e.g., an artificial kidney, which returns thefiltered blood to circulatory system of the individual implanted withthe in vivo filtration device (e.g., artificial kidney) or directlyconnects to a blood vessel of the individual. In certain embodiments,the filtration channels are arranged in a substantially parallel-platelike arrangement.

In certain embodiments, the extended inlet manifold includes a firstregion and a second region enclosing a space or lumen defining a conduitthrough which blood can flow. The first region may include asubstantially circular opening forming an inlet configured forconnection to a blood vessel of an individual into whom the in vivofiltration device (e.g., an artificial kidney) is implanted. The firstregion of the extended inlet manifold may also include a transitionregion in which the circular opening transitions into a flattened shapehaving a substantially rectangular cross section in order to guide theblood flow into the substantially rectangular cross section region. Assuch, the lumen enclosed by the extended inlet manifold transitions fromhaving a circular cross-section into a flattened substantiallyrectangular cross-section. The second region of the extended inletmanifold starts at the point where the transition into the substantiallyrectangular cross section is complete and at which point, along theextended inlet manifold, the cross section area of the conduit definedby the extended inlet manifold is constant. The second region of theextended inlet manifold includes a curved region having thesubstantially rectangular cross section and further includes a linearregion having a plurality of openings fluidically connected to theplurality of filtration channels. In certain cases, the linear region ofthe second region may have a tapering configuration in which at leastthe height of the rectangular cross section decreases. In certainembodiments, in addition to a decrease in height of the rectangularcross section of the linear region of the second region of the extendedinlet manifold, the width may also decrease. The plurality of channelsis in fluidic communication with an outlet manifold having a firstregion and a second region. The first region may have a substantiallyrectangular cross section that is connected to the plurality ofchannels. The second region of the outlet manifold may include an outlethaving a substantially circular cross section and a transition area inwhich the rectangular cross section of the outlet manifold transitionsinto a substantially circular cross section. The outlet may beconfigured for connecting to a bioreactor chamber of the in vivofiltration device such as an artificial kidney which returns thefiltered blood to a blood vessel of the individual implanted with the invivo filtration device. The inlet of the hemofilter may be adjacent tofacilitate connecting the inlet and outlet of the hemofilter to adjacentblood vessels of the individual. For example, the inlet and outlet ofthe hemofilter may be positioned for connection to renal artery andrenal vein, respectively, of an individual.

In certain embodiments, the inlet of the first region of the extendedinlet manifold may be have a standard geometry compatible for connectingto a blood vessel of an individual. In certain aspects, the inlet may besubstantially circular. As used herein, the phrase substantiallycircular refers to a circular shape or an oval shape formed upon slightcompression of the circular opening. The diameter of the inlet may rangefrom 3 mm-8 mm and may be selected based upon the blood vessel to whichthe in vivo filtration device will be connected. In certain embodiments,the diameter of the inlet may range from 3 mm-7 mm, 3 mm-6 mm, 3 mm-5mm, 4 mm-7 mm, or 4 mm-6 mm. The inlet may be grafted (e.g., sewed)directly to a blood vessel or may be connected to a biocompatible tubingthat in turn is grafted to a blood vessel.

The first region of the extended inlet manifold may include a transitionregion where the circular cross section at the inlet transitions into asubstantially rectangular cross section that has a decreased heightcompared to the diameter of the inlet and an increased width compared tothe diameter of the inlet. The term “substantially rectangular” as usedherein refers to a rectangular shape that has a width that is largerthan the height and corners that are either rounded or form a 90° angle.The dimensions of the substantially rectangular cross section region ofthe extended inlet manifold at the first region may be about 2 mm-8 mmheight and 5 mm-10 mm in width (transitioning from a diameter of 3 mm-8mm, respectively) and may transition to a substantially rectangularcross section having a dimension at the start of the second regionranging from 7 mm-50 mm in width and 0.5 mm-8 mm height. In certainembodiments, the diameter of the inlet may range from 4 mm-7 mm and therectangular cross section at the start of the second region may rangefrom 0.5 mm-3 mm height and 20 mm-50 mm width, e.g., 0.5 mm-2.5 mmheight and 20 mm-40 mm width, 0.5 mm-2 mm height and 20 mm-35 mm width,0.75 mm-2 mm height and 25 mm-35 mm width, or 1 mm-2 mm height and 25mm-30 mm width. In certain embodiments, the first region may alsoinclude a turn to change the direction of flow of blood as compared tothe direction of the flow of blood at the inlet. For example, the firstregion may include an L-shaped turn or a curvature between 60°-120° thatchanges the direction of blood flow by an angle of about 60°-120°compared to the direction of blood flow at the inlet.

The second region of the extended inlet manifold may include a U-shapedregion that further changes the direction of blood flow where the changeof direction is at an angle of 150°-210° compared to the direction ofblood flow at the end of the first turn (e.g., L-shaped turn).

The second region of the extended inlet manifold after the U-shaped turnincludes a tapered region that decreases in cross section area from aproximal region to a distal region. As used herein proximal region isthe region closer to the inlet of the device and a distal region isfarther from the proximal region. In certain aspects, the tapered regiondecreases in height from the proximal region towards the distal regionwith or without a decrease in width of the region thereby decreasing thecross-sectional area of the conduit defined by the manifold. In certainembodiments, the height of the second region may decrease such that asthe blood is distributed into the plurality of channels and the volumeof blood in the extended inlet manifold decreases, the decreased height(and the decreased cross section area) of the extended inlet manifoldensures maintenance of blood flowing into subsequent downstream channelssuch that the rate of blood flow in each of the plurality of channels issubstantially comparable. As used herein, the term “downstream” refersto a location towards which the blood is flowing after it flows throughthe U-shaped turn in the second region of the extended inlet manifold.The tapered end of the extended inlet manifold may lead into the last ofthe plurality of filtration channels while the remainder of theplurality of channels extends from periodically placed openings in theextended inlet manifold. In certain embodiments, the first channel ofthe plurality of channels may be referred to as a top channel and thelast channel may be referred to as bottom channel.

In certain embodiments, the plurality of filtration channels are spacedapart by a predetermined distance along the second region of theextended inlet manifold, where the predetermined distance is constant orvariable (the distance may increase or decrease from one channel toanother). The distance of separation between the channels can bedetermined based upon a number of factors, such as, the number ofchannels, the length of the second region, the surface area of themembrane portion of the channels and so forth. In some embodiments, thechannels are spaced apart by 0.50 mm-2 mm along the second region of theextended inlet manifold. In certain aspects, the flow rate of bloodthrough the channels may be controlled further by including an optionalindent in the extended inlet manifold which reduces the cross sectionalarea of the conduit defined by the extended inlet manifold at theentrance of a filtration channel. For example, indents may be arrangedperiodically along the second region of the extended inlet manifold(after the U-shaped turn) such that the cross section (height) of theregion is decreased proximate the opening for the filtration channelspositioned at the level of the indent. In certain embodiments, theindent may reduce the cross sectional area of the extended inletmanifold at the entrance to each of the plurality of filtration channelsby 1% to 25% compared to the cross sectional area immediately upstreamto the opening to the channel.

In certain embodiments, the height of the tapered section of the secondregion of the extended inlet manifold (after the U-shaped turn) maydecrease in a range of a quarter to an eighth of the initial height(height before start of the tapering). In certain embodiments, theheight of the end of the tapered section (e.g., at the last channel) maybe a quarter to an eighth of the initial height (height before start ofthe tapering). In certain embodiments, the height of the second regionof the extended inlet manifold may be determined by the desired flowrate of blood traversing through the manifold. For example, the heightof the substantially rectangular cross section may be set at square rootof local volume flow rate, i.e., the height may be decreased tocompensate for the decrease in the local volume of blood at eachlocation downstream to an opening feeding into a filtration channel. Incertain embodiments, the height of the conduit decreases with the squareroot of volumetric flow rate:(h=local volume flow rate^(0.5)),  (Equation 1),

where h is the conduit height in the tapered section 5. In certainembodiments, the height of the conduit 5 decreases linearly with thelocal volumetric flow rate:Local volume flow rate=h×w×local average velocity  (Equation 2),

where h is the conduit height, and w is the conduit width.

In certain embodiments, instead of or in addition to the second regionof the extended inlet manifold decreasing in height, it may decrease inwidth such that the width decreases by a factor of 0.9-0.75 of thestarting width. In certain embodiments, the width of the end of thetapered region (e.g., at the last channel) may be at the width at thebeginning of the tapering second region or may decrease by a factor of0.9-0.75 times the width at the start of the tapered section.

The plurality of filtration channels may define a conduit having arectangular cross section. The width of the filtration channels may becomparable to the width of the tapered section of the extended inletmanifold. The height of the rectangular filtration channels may be inthe range of 0.5 mm-5 mm (e.g., of 0.5 mm-4 mm, 1 mm-4 mm, 1 mm-3 mm, 1mm-2 mm, 1.5 mm-2 mm, 1 mm-2 mm, or 0.5 mm-2 mm) and the width of therectangular filtration channels may be in the range of 8 mm-50 mm (e.g.,9 mm-50 mm, 10 mm-50 mm, 10 mm-40 mm, or 20 mm-40 mm). The length of thefiltration channels can vary based on a number of factors, such as, thesurface area of the membrane section in the filtration channels, theheight and width of the channels as well as the number of channels. Incertain embodiments, the length of the channel may be in the range of 40mm-100 mm (e.g., 40 mm-90 mm, 40 mm-80 mm, 40 mm-70 mm, or 50 mm-70 mm).The portion of the filtration channels where a membrane forms the wallsof the channels may be vary depending upon the dimensions and number ofthe channels. In certain embodiments, at least a quarter, at least ahalf, at least a two third, or more of the channel is formed from amembrane. In certain embodiments, the plurality of channels may includea surface area of between 0.016 and 0.16 square meters that includes amembrane. In certain embodiments, the plurality of channels may eachhave a membrane section providing a surface area of 0.0008 m²-0.008 m²per channel for filtration of blood flowing through the channels. Incertain embodiments, the plurality of channels in the hemofilter mayprovide a filtration area (formed by the membrane) in the range of 0.016m²-0.16 m², e.g., 0.032 m²-0.16 m², 0.064 m²-0.16 m², 0.064 m²-0.10 m²,or 0.064 m²-0.09 m². The number channels may be 4 or more, such as up to50, e.g., 5-40, 5-30, 5-25. In certain examples, the number of channelscan be in the range of 10-40 channels, such as, 10-35 channels, 10-30channels, 15-40 channels, or 15-30 channels. As noted herein, the numberof channels can be increased and at least one of length or width of thechannels decreased or vice versa to provide a target filtration surfacearea.

The membrane portion of the filtration channels may be affixed to ascaffold for connecting to the inlet and outlet manifolds of thehemofilter. In certain aspects, the scaffold may define two side wallsof the channel and an enclosed inlet and outlet of the channels and mayprovide open top and/or an open bottom which may be covered by themembrane to provide the filtration surface. The membrane used forfiltration may be a biocompatible membrane used in the field of dialysisand/or ultrafiltration, such as, silicone membrane, silicon nanoporemembrane (SNM), silicon nitride, silica, atomically thin membrane suchas graphene, silicon, silicene, molybdenum disulfide (MoS₂), etc., or acombination thereof, or a polymer. The membrane may be a planar membraneis affixed to the scaffold. In certain aspects, the planar membrane maybe folded into a tube having a rectangular cross section. In certainaspects, the planar membrane is not a hollow fiber like membrane whichprovides a minimal surface area for filtration and requires use of 10000hollow fibers that are over 150 mm in length which is not suitable foran implantable filtration device, such as, an artificial kidney.

As noted herein, the plurality of channels may be in a stackedconfiguration where the channels are substantially parallel to eachother and may be oriented at an angle with reference to the secondregion of the extended inlet manifold. For example, the angle betweenthe tapered section and the top surface of the filtration channels maybe about 90 degrees-150 degrees and the angle between the bottom surfaceof the filtration channels and the tapered section may be about 90degrees-30 degrees. The connection between the tapered section of thesecond region of the extended inlet manifold and the plurality offiltration channels define walls that are linear or curved. In certainaspects, the plurality of filtration channels may be connected to thetapered section via a curved flow path where the blood traversingthrough the tapered section changes direction by less than 90 degrees toenter the plurality of channels. The curved flow path may be provided byincluding a curved conduit that gradually changes the direction of bloodflow. Thus in certain aspects, a curving flow path connects the inletmanifold to the plurality of filtration channels. The curving flow pathmay have a substantially rectangular cross section geometry and may havea width that is comparable to width of the tapered section of themanifold and/or width of the filtration channels or a width shorter thanthe width of the tapered section of the manifold and/or width of thefiltration channels. In certain embodiments, the curving flow path maybe provided by a curved region of the filtration channels. In such anembodiment, the filtration channels may include a first curved sectionthat includes a curved top surface and a curved bottom surface and twoside walls extending between the top and bottom curved surfaces, wherethe curved top surface forms an obtuse angle with the tapered section ofthe extended inlet manifold; a linear section that includes a planar topsurface and planar bottom surface and two side walls extending betweenthe top and bottom planar surfaces; and a second curved section thatincludes a curved top surface and a curved bottom surface and two sidewalls extending between the top and bottom curved surfaces, where thecurved top surface forms an acute angle with a reverse-tapered sectionof the outlet manifold. In such embodiments, at least a portion of thelinear section may include a membrane for filtration of blood.

In certain embodiments, the top and bottom curved surfaces of the firstcurved section of the plurality of filtration channels may be spacedapart to define a conduit having a substantially constant cross sectionarea or may be spaced to provide a smaller cross section area at theentrance of the channels which cross section area increases towards thelinear section of the filtration channel. The pinched or constrictedentrance may facilitate even distribution of the blood into theplurality of channels.

In certain embodiments, the top and bottom curved surfaces of the secondcurved section of the plurality of filtration channels may be spacedapart to define a conduit having a substantially constant cross sectionarea or may be spaced to provide a smaller cross section area at theexit of the channels which cross section area decreases from the linearsection of the filtration channel towards the reverse-tapered outletmanifold. The pinched or constricted exit may facilitate drainage of thefiltered blood into the outlet manifold at a slower speed and provide alonger time for filtration across the membrane in the linear section ofthe channels.

As noted above, the outlet manifold may include a first region that isreverse-tapered such that the cross section area of the first regionincreases from the proximal end (where a first filtration channel or thetop channel of the plurality of channels is connected to the outletmanifold) towards the distal end. The dimensions of the reverse-taperedsection of the outlet manifold may be same or similar to that of thetapered section of the extended inlet manifold. The first region of theoutlet manifold may have a substantially rectangular geometry similar tothe tapered section of the extended inlet manifold. The second region ofthe outlet manifold may include a transition region in which therectangular cross section of the outlet manifold changes into a circularcross section at the outlet of the hemofilter. The outlet may becircular and have a diameter comparable to that of the inlet. Thereversed tapered section of the outlet manifold may be substantiallyparallel to the tapered section of the inlet manifold.

Hemofilter such as those depicted in FIGS. 1-23 were designed andadvanced Computational Fluid Dynamic (CFD) tools were used to modelblood flow through such hemofilters. The CFD models incorporatedpulsatile flow boundary conditions based on in vivo ultrasoundmeasurements of blood flow.

FIGS. 1-23 illustrate embodiments of a hemofilter comprising an extendedinlet manifold, an outlet manifold, and a plurality of channels betweenthe extended inlet manifold and outlet manifold.

FIG. 1 depicts a hemofilter that includes an extended inlet manifoldhaving a first region 1 with a substantially circular opening forming aninlet 33 configured for connection to a blood vessel of an individualinto whom the filtration device is implanted. The first region 1includes a transition region in which the inlet conduit transitions froma circular cross-sectional geometry to a flattened shape with asubstantially rectangular cross-sectional geometry. The second region ofthe extended inlet manifold has the substantially rectangular crosssection geometry and includes a U-shaped turn 4 that leads into atapered section 5 of the extended inlet manifold which includes aplurality of openings fluidically connected to the plurality offiltration channels 30. The plurality of filtration channels are in astacked and substantially parallel configuration. The plurality offiltration channels are fluidically connected to a first region 6 of anoutlet manifold that has substantially rectangular cross sectiongeometry and a plurality of openings from connection to the plurality offiltration channels. The first region 8 of the outlet manifold includesa reverse taper where the rectangular cross section geometry of thefirst region 8 of the outlet manifold increases in area towards a secondregion 2 of the outlet manifold. The second region 2 of the outletmanifold includes a transition area in which the rectangular crosssection of the outlet manifold transitions into a substantially circularcross section forming an outlet 34 that connects to a blood vessel ofthe individual.

Aspects of the extended inlet and outlet include a smooth transition ofthe inlet conduit from a circular cross-sectional geometry to arectangular cross-sectional geometry that enable maintenance of wallshear stress above values needed to minimize the potential for thrombusformation. In some embodiments, the wall shear stress needed to minimizethe potential for thrombus formation is greater than 10 dyne/cm².

FIG. 2 provides another view of the extended inlet manifold hemofilterdepicted in FIG. 1. FIG. 2 shows the U-shaped turn 4 in second region ofthe extended inlet manifold that changes the blood flow direction byabout 150 to 210 degrees with reference to the direction of blood flowin the transition area of the first region. FIG. 2 also shows thetapered section 5 of the second region of the extended inlet manifold.In certain embodiments, the height of the conduit 5 decreases with thesquare root of volumetric flow rate:(h=local volume flow rate^(0.5)),  (Equation 1),

where h is the conduit height in the tapered section 5. In certainembodiments, the height of the conduit 5 decreases linearly with thelocal volumetric flow rate:Local volume flow rate=h×w×local average velocity  (Equation 2),

where h is the conduit height, and w is the conduit width.

FIG. 3 provides a side view of a hemofilter showing tapered conduit 6where the height as well as width of the conduit decreases. In suchembodiments, the inlet manifold conduit width decreases from initialvalue range between 7.5 mm and 50 mm to a final value range between 7 mmand 40 mm.

FIG. 4 depicts a hemofilter where extended inlet manifold is shaped toinclude a U-turn 3 to change blood flow direction by about 60 to 120degrees with reference to the initial direction of the blood flow. Theextended inlet manifold includes only a single turn instead of the twoturns as shown in FIGS. 1 and 2 as this embodiment of the hemofilterincludes fewer filtration channels (six verses twenty) and hence twoturns are not needed to provide adjacent placement of the inlet andoutlet openings. As used herein, adjacent in the context of positioningof the inlet and outlet of a hemofilter refers to placement at distanceseparated by less than 10 cm, less than 5 cm, or less than 1 cm.

FIGS. 5A-5B provide an alternate design of a hemofilter manifold. FIG.5A shows a tapering conduit 7 having regularly placed indents 77 thatdecrease the cross-sectional area of the conduit at the entrance to eachof the filtration channels. FIG. 5B shows a zoomed in schematic of thedecrease in the cross-sectional, as depicted by the double headedarrows.

FIG. 6 shows a schematic of hemofilter inlet manifold connected to aplurality of channels arranged in a spaced apart, parallel stackedconfiguration. The second region 32 of the extended inlet manifold isslanted relative to the longitudinal length of the filtration channels30 at an angle 31 that is less than 90 degree and greater than 45degree.

FIGS. 7A-7B depict a partial view of an extended inlet manifolddepicting a tapered section connected to a plurality of filtrationchannels that are arranged in a parallel stacked configuration. A firstcurved region 8 of the plurality of filtration channels is indicated. Alinear broken line 9 is included to illustrate the end of the curvedsection and beginning of the planar section of the filtration channels.FIG. 7B illustrates a zoomed-in image of the curved conduit section atthe inlet of the plurality of filtration channels. FIG. 7B, showstransitional curved flow conduits 10 providing a guide flow between theinlet manifold and parallel channels, where the top surface of thecurved region 10 is at a tangent to the inner surface 11 of the inletmanifold.

FIG. 8 depicts the height of curved transitional region 12 of the firstcurved section of the plurality of the filtration channels. The length13 of the first curved section of the plurality of the filtrationchannels is also depicted. As noted herein, in some embodiments, heightof the curved region can be in the range between 0.2 mm and 1.8 mm andthe height of the channel may expand to a height in the range between0.25 mm and 2 mm over the length of the filtration channel. In someembodiments, the height of the curved transitional region may increasefrom the inlet toward the filtration section of the channels. In someembodiments, the width of the curved transitional flow conduit may varyover the length. In such embodiments, the width varies from a valuerange between 8 mm and 50 mm at the entry to a value range between 7 mmand 40 mm over the length.

FIG. 9 shows a schematic of hemofilter with extended inlet manifold anda parallel-plate arrangement of the filtration channels according toembodiments of the present invention. Specifically, FIG. 9 shows aninlet manifold conduit 32 and a plurality of parallel conduits orchannels 30 at an angle of orientation 31 relative to inlet manifoldconduit 32. The orientation of the hemofilter is flipped compared to theorientation depicted in FIG. 6.

FIG. 10 provides a view of the outlet manifold of a hemofilter inaccordance to the embodiments of the present invention. FIG. 10 depictsa configuration where blood is delivered from the multiple parallelplate channels with a rectangular cross-sectional geometry with a curvedsection 14 that connects to the outlet manifold. The dashed lines 15demarcated the end of the linear section of the filtration channel andthe start of the curved section. Additionally, FIG. 10 shows a taperedoutlet manifold 16, where the cross-sectional area of the manifoldincreases over the length. The height of the outlet manifold conduit 16increases from an initial height of between 0.25 mm and 2 mm to a finalheight between 1 mm and 10 mm. The height of the outlet manifold conduitincreases with the square root of volumetric flow rate as described inEquation 1. Height of the manifold conduit may also increase linearlywith a local volumetric flow rate as described in Equation 2.

FIG. 11 provides a hemofilter in accordance to the embodiments of thepresent invention. Specifically, the hemofilter of FIG. 11 depicts aninlet 33, an outlet 34 and six filtration sections between the inlet andoutlet.

FIG. 12 provides a hemofilter in accordance to the embodiments of thepresent invention. Specifically, the hemofilter of FIG. 12 depicts anextended inlet manifold with opening 33, an outlet manifold with opening34, and twenty filtration channels between the inlet and the outlet. Thechannels of the plurality of channels have a length of 65 mm, a heightof 0.5 mm, and a width of 30 mm.

FIG. 13 provides a hemofilter in accordance to the embodiments of thepresent invention. Specifically, the hemofilter of FIG. 13 depicts apart of the extended inlet manifold with opening 33, an outlet manifoldwith opening 34 and twenty channels between inlet and outlet manifolds.

FIG. 14 provides a side view of the hemofilter of FIG. 13, illustratinga first (top) channel 35 and the last (bottom) channel 36.

FIGS. 15-17, and 19-23 provide CFD modeling of the hemofilter with theextended inlet in accordance to the embodiments of the presentinvention, illustrating transient simulations, laminar flow, and varyingboundary conditions. Parameters of the CFD modeling for FIGS. 1-22include laminar flow with a low Reynolds number flow. Inlet conduitparameters include a physiology-based pulsatile flow rate with a meanflow rate of 750 ml/min for the full hemofilter device, and a maximumflow rate of 827 ml/min for the full hemofilter device. Outletparameters include an average static pressure of 0 mmHg. Additionally,CFD modeling was applied with parameters representing non-Newtonianblood at 37° C. using a cross-non-Newtonian viscosity model at a densityof 1060 kg/m³. The cross-non-Newtonian viscosity model included aninfinite shear limit of 3.5 cps and a zero shear limit of 56.0centipoise (cps). The CFD modeling of the hemofilter with the extendedinlet in accordance to the embodiments of the present invention showedgood distribution of flow amongst the channels (−10.8% to +5.5%), wherethe initial top five channels 1-5 had the lowest volumetric flow rates.Additionally, few areas in the hemofilter device had sustained low shearstress, specifically at the inlet diffuser and the entrance and exitfrom the channels. Lastly, the hemofilter device had a low pressure dropof 6 mmHg at a maximum flow rate of 827 ml/min, which helps maintainarterial driving pressure for ultra-filtration.

FIG. 15 illustrates the speed contours of blood on an XY-symmetry plane,showing a smooth transition from inlet and outlet conduits to the flowchannels. Inlet conduit shows an initial high fluid velocity in therange of 0.26-0.29 m/sec at the entrance of inlet conduit and decreasesto a range of 0.03-0.09 m/sec as it flows to the end of inlet conduitand into the flow channels. Outlet conduit shows a fluid velocity in therange of 0.26-0.29 m/sec along the center of outlet conduit anddecreases as blood flows into the channels.

FIG. 16 provides a zoomed in image of FIG. 15. The arrows in FIG. 16illustrate lower speed regions and lower wall shear stress regions alongtop walls entering the channels.

FIG. 17 provides an illustration of the flow velocity in the channels atthe maximum volumetric flow rate of 827 ml/min (0.518 seconds timestep), showing good flow uniformity amongst channels, with slower flowvelocities through the top 5 channels.

FIG. 18 provides a bar graph for volumetric flow rate variation in eachchannel in a hemofilter comprising 20 parallel channels extending fromthe second region of the extended inlet manifold. The data shows overallgood uniformity of flow amongst channels, with lower flow rates inchannels 1-5 (top channels nearest the incoming flow).

FIG. 19 provides an illustration of the static pressure contours in thehemofilter device. The volumetric flow rate tested was 827 ml/min, at0.518 seconds, showing high pressure between 5.63-6.26 mmHg in the inletconduit and lower pressures between about 1.70-0 mmHg in the outletconduit.

FIG. 20 shows regions of lower wall shear stress in the hemofilterdevice. Channel walls have a wall shear stress at least 10 dyne/cm².Additionally, the regions at the entrance and exit of the channels havean even lower shear stress of about 8 dyne/cm².

FIG. 21 provides an illustration of the low wall shear stress regions inthe hemofilter. The channel walls have a wall shear stress of at least10 dyne/cm² and areas of low shear stress are present at the entranceand exit of the channels, and very small areas of low shear (0-7dyne/cm²) at the entrance of the channels.

FIG. 22 provides an illustration of blood velocity in the hemofilter.The blood velocity varies at the walls of the channels and conduitscompared to the central area away from the walls. The flow rate rangesfrom 0.06 m/sec-0.28 m/sec in the inlet manifold and slows to a range of0.03 m/sec-0.09 m/sec in the plurality of channels. This image alsoshows regions of low wall shear stress on the hemofilter walls.

FIG. 23 provides an illustration of the platelet stress accumulation(PSA) along particle paths in the hemofilter device, where the highestPSA was shown along the corners and near the walls in the slowest movingregions of the hemofilter. The upper limit of the PSA range was limitedto 3 Pa*sec to visualize the variations. The CFD model input parametersfor the steady state simulations included laminar flow with a lowReynolds number flow; particle tracking with 3 mm diameter plateletparticles, neutrally buoyant particles, and a two-way coupleparticle/flow field model; boundary conditions included an inlet flowrate of 827 ml/min (maximum flow rate), and an outlet average staticpressure of 0 mmHg; and non-Newtonian blood at 37° C. using a crossnon-Newtonian viscosity model and a density of 1060 kg/m3. Thecross-non-Newtonian viscosity model included an infinite shear limit of3.5 cps, and a zero shear limit of 56.0 cps.

Hemofilters with Serpentine Filtration Channel

Embodiments of the hemofilters provided herein include an extended inletconduit, a single serpentine filtration channel, and an outlet conduit.The extended inlet conduit may include a first region having an openinghaving a substantially circular cross section geometry configured forconnection to a blood vessel of an individual into whom the in vivofiltration device is implanted. The first region of the extended inletconduit may also include a transition region in which the circularopening transitions into a substantially rectangular cross section inorder to guide the blood flow into the substantially rectangular crosssection region. As such, the space enclosed by the extended inletconduit transitions from having a circular cross-section into asubstantially rectangular cross-section. The second region of theextended inlet conduit starts at the point where the transition into thesubstantially rectangular cross section is complete and at which point,along the extended inlet conduit, the cross section area is constant.The second region of the extended inlet conduit includes a curved regionhaving the substantially rectangular cross section. The curved sectionof the inlet conduit is connected to a serpentine filtration channelthat includes linear sections connected by turnarounds such that thedirection of flow of blood in the linear sections reverses at eachadjacent linear section connected by a turnaround section. In someembodiments, the curved section of the inlet conduit may lead into asubstantially planar section of the first filtration section of theserpentine channel. In some embodiments, the curved section of the inletmay include a U-shaped curve, providing a turnaround section similar tothose in the serpentine channel, see e.g., FIG. 24. In otherembodiments, the curved section of the inlet conduit connected to alinear section of the serpentine channel may include a curve thatconnects the inlet to the first filtration section of the serpentinechannel at an angle of about 90 degree, see e.g., FIG. 25.

In certain embodiments, a hemofilter having a serpentine filtrationchannel may have an extended inlet with two turnaround sections. Theextended inlet may include a first transition region separated from asecond transition region by a first turnaround section. The secondtransition region may terminate in a second turnaround section connectedto a substantially planar section of the first filtration section of theserpentine channel. The first transition region may have a circulateopening for connecting to a blood vessel, which circular openingflattens in height and expands in width to produce a substantiallyrectangular shape which is connected to the second transition region viathe first turnaround section. The lumen of the inlet in the secondtransition region increases in cross sectional area by expansion ofwidth of the lumen and terminates in the second turnaround such that thedimensions of the cross-section of the lumen of the inlet at the end ofthe second transition region and the second turnaround section aresubstantially the same and such that the cross sectional dimension ofthe lumen of the second turnaround area matches that of the filtrationsections of the serpentine channel. A hemofilter with an extended inletwith two turnaround sections of different size is depicted in FIGS. 76Aand 76B. Cross section area here refers to the area of the interior ofthe conduit, i.e., lumen of the conduit.

The serpentine channel may have a substantially rectangular crosssection through which blood flows in the channel and may include a firstlinear section followed by a first turnaround, followed by a secondlinear section, followed by a second turnaround and so forth and thelast linear section or the last turnaround may be connected to an outlethaving a first region that is substantially rectangular and a secondregion that transitions from rectangular to a circular cross section toterminate in a circular outlet configured for connection to a bloodvessel of the individual. The linear sections of the serpentine channelmay be in a stacked spaced-apart arrangement and may be substantiallyparallel to each other.

One or more curves or turns may be included in the inlet and the outletconduits to provide a hemofilter in which the inlet and outlet openingsare placed adjacent to each other to facilitate connecting the in vivofiltration device to the blood vessels of the individual, for example,for connecting the in vivo filtration device comprising the hemofilterwith adjacent inlet and outlet openings to an artery and a vein,respectively, of the individual, see, e.g., FIG. 25.

The dimensions of the inlet opening, outlet opening, and rectangularcross section areas may be as provided for the hemofilter with extendedinlet manifold in the preceding section. For example, the diameter ofthe inlet may range from 3 mm-8 mm and may be selected based upon theblood vessel to which the in vivo filtration device will be connected.In certain embodiments, the diameter of the inlet may range from 3 mm-7mm, 3 mm-6 mm, 3 mm-5 mm, 4 mm-7 mm, or 4 mm-6 mm. The inlet may begrafted (e.g., sewed) directly to a blood vessel or may be connected toa biocompatible tubing that in turn is grafted to a blood vessel.

The dimensions of the substantially rectangular cross section region ofthe inlet conduit at the first region may be about 2 mm-8 mm height and5 mm-10 mm in width (transitioning from a diameter of 3 mm-8 mm,respectively) and may transition to a substantially rectangular crosssection having a dimension at the start of the second region rangingfrom 7 mm-50 mm in width and 0.5 mm-8 mm height. In certain embodiments,the diameter of the inlet may range from 4 mm-7 mm and the rectangularcross section at the start of the second region may range from 0.5 mm-3mm height and 20 mm-50 mm width, e.g., 0.5 mm-2.5 mm height and 20 mm-40mm width, 0.5 mm-2 mm height and 20 mm-35 mm width, 0.75 mm-2 mm heightand 25 mm-35 mm width, or 1 mm-2 mm height and 25 mm-30 mm width.

The serpentine channel may have a width that substantially matches thewidth of the rectangular second region of the inlet conduit and therectangular first region of the outlet conduit. In certain aspects, theheight of the linear sections of the serpentine channel may becomparable to the height of the rectangular second region of the inletconduit and the rectangular first region of the outlet conduit. Forexample, the linear section of the filtration channel may have a heightin the range of 0.5 mm-5 mm (e.g., of 0.5 mm-4 mm, 1 mm-4 mm, 1 mm-3 mm,1 mm-2 mm, 1.5 mm-2 mm, 1 mm-2 mm, or 0.5 mm-2 mm) and the width in therange of 8 mm-50 mm (e.g., 9 mm-50 mm, 10 mm-50 mm, 10 mm-40 mm, or 20mm-40 mm). The length of the filtration channels can vary based on anumber of factors, such as, the surface area of the membrane section inthe filtration channels, the height and width of the channels as well asthe number of channels. In certain embodiments, the length of each ofthe channel may be in the range of 40 mm-100 mm (e.g., 40 mm-90 mm, 40mm-80 mm, 40 mm-70 mm, or 50 mm-70 mm). The portion of the filtrationchannels where a membrane forms the walls (e.g., top and bottom walls)of the channels may vary depending upon the dimensions and number of thelinear sections of the channels. In certain embodiments, at least aquarter, at least a half, at least a two third, or more of the linearsection of the channel is formed from a membrane. In certainembodiments, a surface area of between 0.016 and 0.16 square meters ofthe channel may be covered by a membrane. In certain embodiments, thelinear sections of the serpentine channel may each have a membranesection providing a surface area of 0.0008 m²-0.008 m² per linearsection for filtration of blood flowing through the channel. In certainembodiments, the serpentine channel in the hemofilter may provide afiltration area (formed by the membrane) in the range of 0.016 m²-0.16m², e.g., 0.032 m²-0.16 m², 0.064 m²-0.16 m², 0.064 m²-0.10 m², or 0.064m²-0.09 m². The number of repeats of the linear regions separated by theturnaround regions can be in the range of 10-40, such as, 10-35, 10-30,15-40, or 15-30. As noted herein, the number of linear regions can beincreased and at least one of length or width of the channel decreasedor vice versa to achieve a target filtration surface area for thehemofilter.

In certain embodiments, the membrane portion of the linear sections ofthe serpentine channel may be affixed to the turnaround sections. Incertain aspects, the membrane may be attached to a scaffold defining twoside walls of the linear section of the channel and providing an opentop and/or an open bottom which may be covered by the membrane toprovide the filtration surface.

The flow of blood through the linear sections for filtration may bedetermined by the shape and angle of curvature of the turnaroundsections and/or height of the turnaround sections. In a first aspect,the turnaround region may include a constriction at the beginning of theturnaround region where the height of the channel is reduced and anexpansion at the end of the turnaround region at which the height of thechannel returns to the height prior to start of the turnaround region.In this aspect, the rate of blood flow into the turnaround region isreduced by the constriction and increased by the expansion. In thisaspect, optionally, the radius of curvature of the inner wall of theturnaround region may be constant or may increase from the beginning tothe end of the turnaround region. The increase in the radius ofcurvature may result in the blood moving through the X-X plane that islower than the X-X plane of the linear section and hence the blood movesfrom a lower plane to a slightly higher plane. In certain cases, theconstriction may reduce the channel height by about 1%-50% and theexpansion may restore the reduction in the height.

In certain aspects, the turnaround region may have an inner radius ofcurvature (defined by the inner wall of the turnaround region) equal toor greater than half the distance between the adjacent parallel linearfiltration sections of the serpentine channel. R=C*S; where R equals theinner radius of curvature, C equals a constant value between 0.5 and 4,S equals the spacing between adjacent parallel linear filtrationsections.

In another aspect, the rate of flow of blood in the serpentine channelmay be controlled by varying height of the channel, where height of thechannel may increase across the linear section of the channel anddecrease around the turnaround section and increase again across thenext linear section of the channel and so forth.

In another aspect, the rate of flow of blood in the serpentine channelmay be controlled by the curvature of the turnaround section, where theturnaround section may include a canted turn at the start of theturnaround section followed by a smoother curvature at the end of theturnaround section. In such an aspect, the height of the channel at theturnaround section may remain the same or may increase, for example, theheight of the channel at the start of the turnaround section may behigher compared to the height before and after the turnaround section.

FIGS. 24-75 illustrate a hemofilter device comprising an extended inletconduit, an outlet conduit, and serpentine flow channel between theinlet and outlet conduits.

CFD modeling of the hemofilter with serpentine channel, such as, thosedepicted in FIGS. 24-75 was performed to assess flow characteristics ofblood flowing through the lumen of the hemofilter. Laminar flow wasobserved based on the CFD modeling. Inlet conduit parameters included aphysiology-based pulsatile flow rate with a mean flow rate of 750 ml/minfor the full hemofilter device, and a maximum flow rate of 827 ml/minfor the full hemofilter device (CFD results). Outlet parameters includedan average static pressure of 0 mmHg. Additionally, CFD modeling wasapplied with parameters representing non-newtonian blood at 37° C. usinga cross-non-Newtonian viscosity model at a density of 1060 kg/m³. TheCFD modeling of the hemofilter with the serpentine channel showed gooddistribution of flow throughout the serpentine channel, where a refinedturnaround geometry eliminated the low shear stress regions within thechannel sections. The pressure drop of 88.5 mmHg was much higher thanthe extended inlet manifold (6 mmHg) of the hemofilter shown in FIGS.1-23.

FIG. 24 provides an illustration of a hemofilter comprising an inletconduit, an outlet conduit, and a serpentine flow channel between inletand outlet conduits. FIG. 24 illustrates a hemofilter device with aserpentine flow channel having six filtration sections each with aheight of 1 mm, a width of 30 mm, and a length of 65 mm. The inlet 33and outlet 34 are circular. The inlet conduit includes a transitionregion in which the circular opening transitions into a substantiallyrectangular cross section. The rectangular cross section region includesa U-turn after which a filtration section of the channel begins.

FIG. 25 provides a hemofilter comprising an extended inlet conduit witha circular opening 33, an outlet conduit with a circular opening 34, anda serpentine channel having 20 rectangular filtration sections eachhaving a height of 1.5 mm, a width of 30 mm, and a length of 65 mm. Afirst region of the extended inlet conduit includes a transition regionin which the circular opening transitions into a substantiallyrectangular cross section. The second region of the extended inletconduit starts at the point where the transition into the substantiallyrectangular cross section is complete and at which point, along theextended inlet conduit, the cross section area is constant. The secondregion of the extended inlet conduit includes a curved region having thesubstantially rectangular cross section. The curved section of the inletconduit is connected to a serpentine filtration channel that includeslinear sections connected by turnarounds such that the direction of flowof blood in the linear sections reverses at each adjacent linear sectionconnected by a turnaround section. The curved section of the inletconduit leads into a substantially planar section of the inlet conduitthat connects to a turnaround section of the serpentine channel.

FIG. 26 provides a zoomed-in view of the inlet conduit and serpentinechannel of FIG. 25.

FIG. 27 provides a further zoomed-in view of the serpentine channel ofFIG. 25 showing the contoured turnaround regions 37 which remove lowshear regions.

FIG. 28 illustrates the speed contours of blood on an XY-symmetry plane,showing smooth flow patterns through the turnaround sections. Inletconduit shows an initial fluid velocity in the range of 0.36-0.83 m/secat the entrance of inlet conduit, with an short region with an increaseof fluid velocity (in the region where the cross-sectional area of theinlet transitions from a circular to a rectangular geometry), followedby a decrease ranging from 0.24-0.36 m/sec as the fluid flows into thefiltration regions of the serpentine channel. Outlet conduit shows afluid velocity in the range of 0.36-0.83 m/sec.

FIG. 29 illustrates speed contours of the serpentine channel of FIG. 28,showing a good transition from the inlet conduit to the serpentinechannel with speed in the range of 0.24-0.48 m/sec, with smooth andrepeatable flow patterns through the turnaround sections.

FIG. 30 illustrates speed contours in the YZ plane, near the turnaroundregions of the serpentine channel with good uniformity and repeatabilityof flow amongst and within the sequential filtration regions ofserpentine channel.

FIG. 31 illustrates the static pressure contours in the XY centerlineplane of the hemofilter, where a pressure drop of 88.5 mmHg occurs,which is significantly higher than 6 mmHg of the extended inlet designof FIGS. 1-23. To reduce the pressure drop, the thickness of the flowpaths within the channel can be increased from 1.5 mm to 2.50 mm, or thehemofilter can have a two system design with 10 filtration regions ineach serpentine channel.

FIG. 32 illustrates the wall shear stress at a low range of about 10dyne/cm².

FIG. 33 illustrates the platelet stress accumulation (PSA) alongparticle paths of the hemofilter with a serpentine channel, showing thehighest PSA along the corners and near the walls in the slowest movingregions of the channels. The results show higher PSA values for theserpentine channel (16 Pa*sec) compared with the extended inlet manifoldof FIG. 23 (3 Pa*sec). The upper limit of PSA range was limited to 16Pa*sec to better visualize the variations in FIG. 33. The CFD modelinput parameters for the steady state simulations included laminar flowwith a low Reynolds number flow; particle tracking with 3 mm diameterplatelet particles, neutrally buoyant particles, and a two-way coupleparticle/flow field model; boundary conditions which included an inletflow rate of 827 ml/min (maximum flow rate), and an outlet averagestatic pressure of 0 mmHg; and non-Newtonian blood at 37° C. using across non-newtonian viscosity model and a density of 1060 kg/m³. Thecross-non-Newtonian viscosity model included an infinite shear limit of3.5 cps, and a zero shear limit of 56.0 cps.

FIG. 34 illustrates channel flow path geometry of the serpentine channeland the turnaround regions.

FIG. 35 illustrates regions of low wall shear stress of anellipse-shaped (ellipse 1) turnaround region of the serpentine channel.FIG. 36 illustrates an inner view of an ellipse (ellipse 1) shapedturnaround region highlighting wall locations with wall shear stressbelow 10 dyne/cm². Shear stress less than 10 dyne/cm² occurs along theouter and inner walls of the turnaround region. FIG. 37 illustratesanother view of an ellipse shaped (ellipse 1) turnaround region showingwall shear stress contours. FIG. 38 illustrates an ellipse shaped(ellipse 1) turnaround region showing fluid velocity (top to bottom) onthe symmetry plane. FIG. 39 illustrates an ellipse shaped (ellipse 1)turnaround region showing fluid velocity in the reverse direction(bottom to top) on the symmetry plane. FIG. 40 illustrates an ellipseshaped (ellipse 1) turnaround region showing velocity vectors (top tobottom) on the XY symmetry plane. FIG. 41 illustrates an ellipse shaped(ellipse 1) turnaround region showing velocity vectors (bottom to top)on the XY symmetry plane.

FIG. 42 illustrates a semi-ellipse shaped turnaround region (ellipse 2)showing wall shear stress contours (top to bottom) on the symmetryplane. FIG. 43 illustrates a semi-ellipse shaped turnaround region(ellipse 2) showing wall shear stress contours (bottom to top) on thesymmetry plane. FIG. 44 illustrates a semi-ellipse shaped turnaroundregion (ellipse 2) showing fluid velocity (top to bottom) on the XYsymmetry plane. FIG. 45 illustrates a semi-ellipse shaped turnaroundregion (ellipse 2) showing fluid velocity in the reverse direction(bottom to top) on the symmetry plane. FIG. 46 illustrates asemi-ellipse shaped turnaround region (ellipse 2) showing velocityvectors (top to bottom) on the symmetry plane. FIG. 47 illustrates apartial ellipse shaped turnaround region (ellipse 2) showing velocityvectors (bottom to top) on the symmetry plane.

FIGS. 48-49 illustrate another partial ellipse shaped turnaround(ellipse 3) showing wall shear stress contours (top to bottom) on thesymmetry plane. FIG. 50 illustrates another partial ellipse shapedturnaround (ellipse 3) showing wall shear stress contours (bottom totop) on the symmetry plane. FIG. 51 illustrates another partial ellipseshaped turnaround (ellipse 3) showing fluid velocity (top to bottom) onthe symmetry plane. FIG. 52 illustrates another partial ellipse shapedturnaround (ellipse 3) showing fluid velocity in the reverse direction(bottom to top) on the symmetry plane. FIG. 53 illustrates anotherpartial ellipse shaped turnaround (ellipse 3) showing velocity vectors(top to bottom) on the symmetry plane. FIG. 54 illustrates anotherpartial ellipse shaped turnaround (ellipse 3) showing velocity vectors(bottom to top) on the symmetry plane.

FIGS. 55-56 illustrate channel flow path geometries of the hemofilterhaving a single serpentine with a plurality of turnaround regionsseparating the filtration regions. The channel height increases acrossthe filtration section 18 and starts to decrease towards the end of eachturnaround region and has the shortest height at the end of theturnaround after which the height increases again across the nextfiltration region 18 and so on. The reduction in area in the turnaroundaccelerates flow around the turnaround avoiding areas of sustained lowwall shear stress which can lead to formation of blood clots. In such anembodiment, the filtration regions are stacked and have a substantiallyparallel configuration channels that deviates by up to 10 degrees from aparallel configuration. In some embodiments, the height of the flowchannel can increase from 1 mm to 2 mm (from start of a filtrationregion to end of the turnaround region) and decrease from 2 mm to 1 mm(from start of the filtration region to start of the next turnaroundregion).

FIGS. 57-58 illustrate channel flow path geometries of the hemofilter.FIG. 59 illustrates static pressure contours of the hemofilter. FIG. 60illustrates XY symmetry plane velocity contours of the hemofilter.

FIG. 61 illustrates inlet conduit and outlet conduit velocity contours,where velocity is at a peak going into the filtration region aftertraversing a turnaround region.

FIG. 62 illustrates streamline velocity contours in the hemofilter.FIGS. 63-64 illustrate velocity vectors at the mid plane of the extendedinlet of the hemofilter. FIG. 63-64 depict a higher velocity where inletconduit is initially necked down from a circular cross section into arectangular cross section, whereas velocity is low along the edge, butblood does not appear to recirculate.

FIG. 65 illustrates velocity vectors at the mid-plane of the outletconduit. FIG. 65 shows a smooth flow into the outlet conduit.

FIG. 66 illustrates wall shear stress contours of the hemofilter,depicting a small region of higher wall shear stress where the inletnecks. FIG. 67 illustrates wall shear stress contours of the hemofilter.

FIG. 68 illustrates resident time on the XY symmetry plane of thehemofilter, where the mass average resident time at the outlet conduitis 9.04 seconds, whereas longer resident times occur along the walls.

FIG. 69 illustrates accumulated stress on the XY symmetry plane of thehemofilter, where accumulated stress is a time integral of viscositytimes strain rate along the channel flow path. The mass averageaccumulated stress at the outlet is 10.6 Pa*sec, whereas higheraccumulated stress was for the blood flow moving near the walls.

FIGS. 70-72 illustrate a hemofilter with a serpentine channel comprisingfiltration regions and a dialysate/ultrafiltrate chamber 23 withparallel plate conduits oriented across from the filtration regions forcollecting molecules that pass through the filter.

FIG. 73 illustrates serpentine channel of a hemofilter and a dialysateconduit 28 that changes flow direction between 150 to 210 degreesbetween alternate stacked regions to maintain counter current dialysisflow arrangement.

FIG. 74 illustrates a hemofilter with a serpentine flow channel in whichthe turnaround regions change flow direction by 150 to 210 degrees ateach subsequent filtration region with reference to the filtrationregions immediately adjacent to the filtration region. The turnaroundregion 17 can have different turn trajectories as depicted.

In some embodiments, the channel height varies through each turn. Insome embodiments, the change in channel height and/or curvature in theflow reversal sections is configured to maintain the desired level ofsustained (time-averaged) wall shear stress along all interior surfacesto minimize the potential for thrombus formation.

FIG. 75 illustrates a hemofilter, where the channel flow shows varyinggeometric profiles (i.e. circular, elliptical, parabolic, spline). Insome embodiments, the channel flow path has configuration 40 comprisinga converging flow path prior to turn, wherein the channel heightdecreases upstream of the channel turnaround by between 0 and 50%. Insome embodiments, the channel flow path has configuration 41, where theinner radius of curvature for the turnaround is equal to or greater thanhalf the distance (S) between adjacent parallel channel walls. In someembodiments, the channel flow path has a diverging flow downstream ofthe turnaround region, where the channel height increases by between 0and 50%. In some embodiments, the channel flow path has configuration42, wherein the channel flow path comprises a diverging flow downstreamof the turnaround region, wherein the channel height increases bybetween 0 and 50%, and the flow returns to the initial height after theturn. The serpentine flow channels have an inner radius (R) of curvatureat a turnaround region 17 (FIG. 75) equal to or greater than half of thedistance between the adjacent parallel conduit walls. Calculation of theinner radius of curvature is shown in Equation 3:R=C×S;

where C is a constant value between 0.5 and 4, R is the inner radius ofcurvature, and S is the spacing between adjacent parallel conduits.

FIGS. 76A and 76B illustrate a hemofilter having a configuration similarto the hemofilter depicted in FIG. 24 but including twenty filtrationsections and an extended inlet having two turnaround sections instead ofa single turnaround section as in FIG. 24. The hemofilter shown in FIG.24 includes an inlet that includes a transition region in which thecross section of the inlet changes from a circular lumen to arectangular lumen, the rectangular lumen connects to a first filtrationsection via a turnaround section which reverses the direction of bloodflow with reference to the direction in a region upstream to theturnaround section. In the hemofilter illustrated in FIGS. 76A and 76B,the extended inlet includes two turnaround sections in the transitionregion, such that, in addition to transitioning from a circular to arectangular lumen, the extended inlet includes two turnaround sectionsthat reverse the direction in which blood flows in the extended inlettwice. In the extended inlet depicted in FIGS. 76A and 76B, the firstturnaround section occurs in a transition region of the extended inletin which the lumen of the inlet is rectangular but has a cross-sectionalarea smaller than the cross-sectional area of the rectangular lumen ofthe inlet at and/or after the second turnaround. The second turnaroundsection connects the first filtration section of the stack to theextended inlet. Therefore, the direction of blood flow is reversed twicein the extended inlet. In contrast, the direction of blood entering thefirst filtration section of the device in FIG. 25, is changed by about90 degrees as compared to the direction in the inlet. A hemofilterhaving the configuration as depicted in FIG. 25 is also referred to as a“Serpentine” hemofilter. A hemofilter having the configuration asdepicted in FIGS. 76A and 76B is also referred to as a “Alt Serpentine”hemofilter.

The hemofilter depicted in FIGS. 76A and 76B includes an extended inletwith two turnaround sections where the cross-sectional area of the inletin the first turnaround section is smaller than the cross-sectional areaof the inlet in the second turnaround section. However, in otherembodiments, the cross-sectional area at both turnarounds may be thesame.

FIG. 77 depicts comparison of linear stress accumulation in hemofilterswith parallel configuration of the filtration channels, a serpentineconfiguration of the filtrations channels, or an altered serpentine(“Alt Serpentine”) configuration. A hemofilter with parallelconfiguration of the filtration channels has an extended inlet manifoldhaving a plurality of filtration channels connected directly to theextended inlet (e.g., see FIG. 1). A hemofilter with serpentinefiltration channel with an inlet connecting with the first filtrationchannel at about a 90 degree angle is referred to as “Serpentine”configuration (see, e.g., FIG. 25). A hemofilter with an extended inlethaving two turnarounds (about 180 degree angle each), wherein the firstturnaround section has a rectangular lumen smaller than the rectangularlumen of the second turnaround section which has a rectangular lumenthat matches the cross section of the filtration channel and isconnected to the serpentine filtration channel is referred to as “AltSerpentine” (see, e.g., FIGS. 76A-76B).

Probability density function (pdf) was used to visualize distribution ofstress accumulation for the collection of particle tracks. PDF is thestatistical distribution of all the stress accumulation values reachedby each individual platelet along its corresponding flow trajectorythrough the device. See Marom and Bluestein, Expert Review of MedicalDevices, 13: 113-122, 2016.

FIG. 78 shows platelet lifetime normalized accumulated stress inhemofilters with Parallel, Serpentine, or Alt Serpentine configuration.FIG. 78 shows that difference in the degree of change in direction ofblood flow in results in a difference in stress accumulation in thehemofilters, with the hemofilters with Parallel (see e.g., FIG. 1) orAlt Serpentine configuration (see, e.g., FIGS. 76A and 76B) having alower normalized accumulated stress as compared to hemofilter withSerpentine configuration (see, e.g., FIG. 25).

In some embodiments, the hemofilters disclosed herein have aconfiguration that allow for blood flow at a low shear stress such thatplatelet accumulated stress remains below the platelet activation limit.Platelet activation limit may be calculated as follows:4.632e-5 τ^(2.30) t,

where τ=shear stress (Pa), t=residence time (s). In some embodiments,the hemofilters provided herein are configured to minimize shear stresssuch that the platelet accumulated stress is below platelet activationlimit. The Parallel or Alt Serpentine configurations such as thosedepicted in FIG. 1 and FIGS. 76A and 76B, respectively have a minimalshear stress such that the platelet accumulated stress is below theplatelet activation limit of 1 while the Serpentine configuration offersa shear stress such that the platelet accumulated stress is above theplatelet activation limit of 1. In some cases, the platelet accumulatedstress may be calculated as described in J. D. Hellums, D. M. Peterson,N. A. Stathopoulos, J. L. Moake and T. D. Giorgio, “Studies on theMechanisms of Shear-Induced Platelet Activation,” Cerebral Ischemia andHemorheology, 1987.

In some embodiments of the hemofilter of the present invention,ultrafiltrate is generated from filtration channels and enters a seriesof parallel plate conduits that remove the ultrafiltrate, draining theultrafiltrate out of the hemofilter.

In some embodiments, ultrafiltrate is generated from parallel platemembranes and enters a series of ultrafiltrate drainage networkcomprising a combination of parallel plate conduits and non-parallelplate conduits. In some embodiments, ultrafiltrate is generated fromparallel plate membranes and enters a series of ultrafiltrate drainagenetworks that do not comprise parallel plate conduits. In someembodiments, the ultrafiltrate exits parallel plate conduits and entersmanifold oriented perpendicular to parallel ultrafiltrate conduits.

In some embodiments, dialysate is distributed to and collected fromparallel plate conduits by a manifold oriented perpendicular to parallelplate conduits. In some embodiments, a dialysate is distributed to andcollected from a network of dialysate conduits comprising a combinationof parallel plate conduits and non-parallel plate conduits. In someembodiments, a dialysate is distributed to and collected from adialysate conduit network that does not comprise parallel plateconduits. In some embodiments, parallel dialysate conduits run betweenblood conduits and are separated by a membrane from a blood conduit onboth the top and bottom. In some embodiments, mass transfer occursthrough both membranes. In some embodiments, the direction of thedialysate flow relative to the blood flow is perpendicular (cross flow),the same (co-current), or the opposite (counter current).

In certain embodiments, the membrane included in the hemofilters (e.g.,hemofilter with serpentine channel or plurality of stacked channels)provided herein may include a plurality of pores having a width in therange of 5 nm-5 micron. In certain embodiments, one or more surface ofthe membrane and or the inner surface of the conduits of the hemofiltersmay be treated to limit protein adsorption. Such a treatment may includetreatments that alter or confer surface charge, surface free energy, ortreatments that promote adhesion of specific cell types. Examples ofsurface treatments can be found, for example, in U.S. Patent ApplicationPublication No. 20090131858, which is hereby incorporated by referencein its entirety.

In certain embodiments, the membrane may include a plurality ofnanopores having a circular or slit shaped opening with a diameter orwidth, respectively, of 1 nm-500 nm, e.g., 1 nm-90 nm, 2 nm-50 nm, 3nm-40 nm, 4 nm-50 nm, 4 nm-40 nm, 5 nm-50 nm, 5 nm-20 nm, 4 nm-20 nm, 7nm-100 nm, 12 nm-20 nm, or 5 nm-10 nm. In certain embodiments, themembrane comprises a plurality of micropores having a circular or slitshaped opening with a diameter or width, respectively, in the range of0.1 μm-5 μm, e.g., 0.1 μm-3 μm, 0.1 μm-0.5 μm, 0.5 μm-1 μm, 1 μm-1.5 μm,1.5 μm-2 μm, 0.1 μm-1 μm, 0.1 μm-0.8 μm, 0.2 μm-0.7 μm, 0.2 μm-0.6 μm,0.2 μm-0.5 μm. In certain embodiments, the plurality of pores are slitshaped and have a width as listed herein and have a length in the rangeof 1 μm-10 μm, e.g., 2 μm-3 μm, 3 μm-4 μm, 4 μm-5 μm, 5 μm-6 μm, 6 μm-7μm, 7 μm-8 μm, 8 μm 9 μm, or 9 μm-10 μm. In certain cases, the slitshaped, i.e., rectangular pores have a depth of 100-1000 nm, a width of3 nm-50 nm and a length of 1 micron-5 micron, e.g., a width×length×depthof 5 nm-50 nm×1 micron-2 micron×200 nm-500 nm. The depth of the poresmay be defined by the thickness of the membrane which may be in therange of 0.1 micron-1000 micron.

The membrane may have any suitable hydraulic permeability for use in thein vivo filtration device, such as an, artificial kidney. In some cases,the hydraulic permeability of the membrane (e.g., SNM) is about 50ml/h/mmHg/m² or greater, e.g., about 75 ml/h/mmHg/m² or greater, about100 ml/h/mmHg/m² or greater, about 150 ml/h/mmHg/m² or greater, about200 ml/h/mmHg/m² or greater, about 250 ml/h/mmHg/m² or greater,including about 300 ml/h/mmHg/m² or greater, and in some cases, is about1,000 ml/h/mmHg/m² or less, e.g., about 900 ml/h/mmHg/m² or less, about800 ml/h/mmHg/m² or less, about 700 ml/h/mmHg/m² or less, about 600ml/h/mmHg/m² or less, including about 500 ml/h/mmHg/m² or less. In someembodiments, the hydraulic permeability of the silicon nanoporousmembrane is from about 50 ml/h/mmHg/m² to about 1,000 ml/h/mmHg/m²,e.g., from about 100 ml/h/mmHg/m² to about 900 ml/h/mmHg/m², from about150 ml/h/mmHg/m² to about 800 ml/h/mmHg/m², from about 200 ml/h/mmHg/m²to about 700 ml/h/mmHg/m², including from about 200 ml/h/mmHg/m² toabout 600 ml/h/mmHg/m².

In certain embodiments, the in vivo infiltration device, such as, abioartificial kidney is dimensioned to fit in a body cavity of asubject. The in vivo infiltration device may be rectangular orcylindrical in shape. In certain case, the in vivo infiltration devicemay have a surface area of 50 cm² or less, such as 10-30 cm², 10-25 cm²,15-25 cm², 20-25 cm², 15-30 cm². In certain cases, the bioartificialkidney may be rectangular and have a length of 3 cm-10 cm, a width of 1cm-6 cm, and a height of 0.3 cm-2 cm, such as dimension(length×width×height) of 3 cm×1 cm×0.5 cm to 6 cm×4 cm×1 cm, e.g., 3cm×1 cm×0.5 cm, S cm×2 cm×1 cm, or 6 cm×4 cm×1 cm. In certainembodiments, the overall dimension of the hemofilter, specifically thefiltration section of the hemofilter, such as those depicted in thefigures provided herein may range from 45 mm-100 mm in height, 80-150 mmin length, and a width of 10-30 mm, such as, height×length×width of45-80 mm×90-130 mm×10-30 mm, respectively.

Any material suitable for encasing in a housing of a in vivoinfiltration device may be used to form the hemofilters provided herein.In some embodiments, the hemofilter may be fabricated, in part, frommedical grade plastic, metals, such as, titanium, stainless steel, etc.

In some embodiments, the hemofilter may be encased in a chamber intowhich an ultrafiltrate produced by filtration of blood in the hemofilteris collected. The chamber may include an opening for draining theultrafiltrate into a blood vessel or one or both ureter of theindividual implanted with the artificial kidney.

In some embodiments the hemofilter may interface with a plurality ofchannels that collect the ultrafiltrate. In some embodiments, theplurality of channels may terminate into a single outlet. In otherembodiments, the plurality of channels may include an inlet forcirculating a dialysis fluid and an outlet for exit of the dialysisfluid. The arrangement of the ultrafiltration and dialysate channels mayinclude a parallel plate assembly as described herein.

In some embodiments, the ultrafiltration/dialysis chamber may include arectangular manifold comprising a plurality of openings connected to aplurality of U-shaped extensions where each U-shaped extension encasesat least the filtration regions of the hemofilter and collects themolecules filtering out of the hemofilter and returns thedialysate/ultrafiltrate to the rectangular manifold for draining out ofthe dialysate/ultrafiltrate.

The flow rate of blood flowing through the hemofilters disclosed hereinmay be in the range of 500 ml/min-2000 ml/min, e.g., 500 ml/min-1500ml/min, 500 ml/min-1000 ml/min, 500 ml/min-900 ml/min, 600 ml/min-900ml/min, or 700 ml/min-900 ml/min. The flow rate of blood flowing throughthe channel(s) of the hemofilters disclosed herein may be in the rangeof 25 ml/min-100 ml/min, e.g., 25 ml/min-75 ml/min, 25 ml/min-70 ml/min,25 ml/min-50 ml/min, 25 ml/min-45 ml/min, or 35 ml/min-45 ml/min.

In certain embodiments, the inlet and outlet manifolds may be shortenedor lengthened based on desired parameters, such as, relative positionwithin the in vivo infiltration device, relative position of thebioreactor chamber of the artificial kidney, etc. Similarly, the inletand outlet conduits of the hemofilter with the serpentine channel may beshortened or lengthened based on desired parameters, such as, relativeposition within the in vivo infiltration device, relative position ofthe bioreactor chamber of the artificial kidney, etc.

Methods

Hemofilters of the present disclosure and in vivo infiltration device,e.g., artificial kidneys that include the same, find use in performinghemodialysis and/or hemofiltration. In general terms, a method forhemodialysis may include connecting a blood inlet and a blood outlet ofthe hemofilter to an individual's circulatory system such that bloodcirculates from the circulatory system, through the channel(s) of thehemofilter, and back into the circulatory system. The connection may bemade at a suitable point in the circulatory system, such as, withoutlimitation, the renal artery and vein. Thus, in some embodiments, theblood inlet is connected to the renal artery, and the blood outlet isconnected to the renal vein. A suitable vascular graft connector may beused to connect the blood inlet and outlet to the circulatory system.

The vascular graft connectors may include any suitable biocompatibletubing for establishing a blood flow between the individual'scirculation and the hemofilter. In some embodiments, the vascular graftconnector includes a polymeric material, including, but not limited to,polyesters, such as polyethylene terephthalate (PET); fluorinatedpolymers, such as polytetrafluoroethylene (PTFE); polyurethanes andcombinations thereof. Suitable polymers include DACRON™ (PET) fromDuPont, and FUSION′ (expanded PTFE and PET) from Maquet. The vasculargraft connectors may have a suitable stiffness so as to provideflexibility for implanting at an implantation site, and to preventexcessive bending that may collapse the inner passageway (i.e., preventkinking).

In some cases, the present method includes implanting the in vivoinfiltration device, e.g., artificial kidney in the body of theindividual. The in vivo infiltration device may be implanted using anysuitable surgical means. In some cases, the in vivo infiltration deviceincludes one or more (e.g., two or more, three or more, or four or more)suture tabs, and the device is positioned in an implantation site bysuturing the in vivo infiltration device to a tissue wall of theimplantation site via the suture tabs. In some embodiments, the in vivoinfiltration device is enveloped in a biocompatible mesh (e.g.,polymeric mesh, such as a polypropylene mesh), and the in vivoinfiltration device is positioned in an implantation site by suturingthe in vivo infiltration device to a tissue wall of the implantationsite via the mesh.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting, since the scope ofthe present invention will be limited only by the appended claims.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

What is claimed is:
 1. A hemofilter for use in filtering blood in vivo,the hemofilter comprising: an extended inlet manifold; a plurality offiltration channels; and an extended outlet manifold, the extended inletmanifold comprising: a first region comprising: a circular inletconfigured for connection to a blood vessel of an individual; and atransition section in which lumen of the extended inlet manifoldtransitions from having a circular cross-section to having a rectangularcross-section; and a second region comprising a U-shaped turn andfollowed by a linear tapered section, the linear tapered sectioncomprising a plurality of openings in fluid communication with theplurality of filtration channels, wherein the plurality of filtrationchannels are arranged in a spaced-apart stacked configuration and are influid communication with a plurality of openings in a first region ofthe extended outlet manifold, wherein the first region of the extendedoutlet manifold is parallel to the linear tapered section of theextended inlet manifold and is reverse-tapered with reference to thelinear tapered section of the extended inlet manifold and wherein theextended outlet manifold comprises a second region comprising: atransition section in which lumen of the extended outlet manifoldtransitions from having a rectangular cross-section to having a circularcross-section; and a circular outlet defined by the circularcross-section of the extended outlet manifold, and wherein thehemofilter is configured for entry of blood through the circular inletand for transporting the blood through the transition section of theextended inlet manifold to the tapered linear section, into theplurality of filtration channels to the first region of the extendedoutlet manifold, into the transition section of the extended outletmanifold, and exit via the circular outlet.
 2. The hemofilter of claim1, wherein channels of the plurality of filtration channels arerectangular and are stacked in a parallel configuration.
 3. Thehemofilter of claim 1, wherein the transition section in extended inletmanifold includes a turn which changes direction of blood flow withreference to the direction in the circular inlet by 60°-120° and/orwherein the U-shaped turn in the second region of the extended inletmanifold changes the direction of blood flow with reference to thedirection in the transition section by 150° and 210°.
 4. The hemofilterof claim 1, wherein the tapered section of the extended inlet manifolddecreases in height and/or the tapered section of the extended inletmanifold decreases in width.
 5. The hemofilter of claim 1, wherein theplurality of filtration channels comprises a first curved regionconnected to the tapered section of the extended inlet manifold, alinear section, and a second curved region connected to areverse-tapered section of the extended outlet manifold, wherein acurvature of the first curved region is opposite to a curvature of thesecond curved region.
 6. The hemofilter of claim 1, wherein theplurality of filtration channels each define a rectangular channel lumenenclosed by a top surface, a bottom surface, and side walls connectingthe top and bottom surfaces, wherein the top surface comprises amembrane for filtration of blood in the rectangular channel lumen and/orthe bottom surface comprises a membrane for filtration of blood in therectangular channel lumen.
 7. The hemofilter of claim 1, wherein thetapered section of the extended inlet manifold and the reverse-taperedsection of the extended outlet manifold and a top channel of theplurality of filtration channels and a bottom channel of the pluralityof filtration channels are arranged in shape of a parallelogram.
 8. Thehemofilter of claim 1, wherein the plurality of filtration channelscomprises 2-50 channels, wherein each of the plurality of filtrationchannels has a length of 10 mm-200 mm, a width of 5 mm-100 mm, and aheight of 0.5 mm-2.5 mm.
 9. A hemofilter for use in filtering blood invivo, the hemofilter comprising: an extended inlet conduit; a singleserpentine filtration channel; and an outlet conduit; the extended inletconduit comprising: a first region comprising: an inlet having acircular cross section shape configured for connection to a blood vesselof an individual; and a transition region in which lumen enclosed by thefirst region transitions from the circular cross section shape into arectangular cross section shape; a second region comprising arectangular cross section and a curved region connected to the singleserpentine filtration channel; the single serpentine filtration channelcomprising: a plurality of filtration sections arranged in aspaced-apart stacked configuration wherein the plurality of filtrationsections are connected via turnaround sections; and the outlet conduitcomprising: first region having a rectangular cross-section; and asecond region that transitions from rectangular to a circular crosssection and terminates in a circular outlet configured for connection toa blood vessel of the individual.
 10. The hemofilter of claim 9, whereinthe plurality of filtration sections each define a rectangular channellumen enclosed by a top surface, a bottom surface, and side wallsconnecting the top and bottom surfaces, wherein the top surfacecomprises a membrane for filtration of blood in the rectangular channellumen and/or the bottom surface comprises a membrane for filtration ofblood in the rectangular channel lumen.
 11. The hemofilter of claim 9,wherein the plurality of filtration sections comprises 2-50 filtrationsections, each disposed between two turnaround sections, wherein each ofthe plurality of filtration sections has a length of 10 mm-200 mm, awidth of 5 mm-100 mm, a height of 0.5 mm-2.5 mm.
 12. The hemofilter ofclaim 9, wherein a curvature of the turnaround sections is non-uniform,circular, or elliptical.
 13. The hemofilter of claim 9, wherein a heightof a filtration section increases from a proximal end, at which bloodenter the filtration section, towards a distal end, at which blood exitsthe filtration section and flows to a turnaround section.
 14. Thehemofilter of claim 9, wherein the extended inlet conduit issubstantially parallel to the plurality of filtration sections andwherein the curved region is a turnaround region that reverses directionof blood flow in a first filtration section with reference to directionof blood flow in the extended inlet conduit and wherein the outletconduit is substantially parallel to the plurality of filtrationsections.
 15. The hemofilter of claim 9, wherein the extended inletconduit is substantially perpendicular to the plurality of filtrationsections and wherein the curved region changes direction of blood flowin a first filtration section to which the blood flows from the inletconduit by about 90 degree relative to the direction of blood flow inthe extended inlet conduit and wherein the outlet conduit issubstantially perpendicular to the plurality of filtration sections. 16.A hemofilter for use in filtering blood in vivo, the hemofiltercomprising: an extended inlet conduit; a single serpentine filtrationchannel; and an outlet conduit; the extended inlet conduit comprising:an inlet; a first transition region; a first turnaround section; asecond transition region; a second turnaround section; wherein in thefirst transition region the inlet transitions from a circular crosssection, configured for connection to a blood vessel of an individual,into a substantially rectangular cross section, wherein the rectangularcross section at the end of the first transition region matches therectangular cross section of the first turnaround section, wherein inthe second transition region the first turnaround section expands inwidth such that a rectangular cross section at the end of the secondtransition region matches a rectangular cross section of the secondturnaround section, wherein the rectangular cross section of the secondturnaround section matches that of the single serpentine filtrationchannel; the single serpentine filtration channel comprising: aplurality of filtration sections arranged in a spaced-apart stackedconfiguration wherein the filtration sections are connected viaturnaround sections; and the outlet conduit comprising: first regionhaving a rectangular cross-section; and a second region that transitionsfrom rectangular to a circular cross section and terminates in acircular outlet configured for connection to a blood vessel of anindividual.
 17. The hemofilter of claim 16, wherein the plurality offiltration sections each define a rectangular channel lumen enclosed bya top surface, a bottom surface, and side walls connecting the top andbottom surfaces, wherein the top surface comprises a membrane forfiltration of blood in the rectangular channel lumen and/or the bottomsurface comprises a membrane for filtration of blood in the rectangularchannel lumen.
 18. The hemofilter of claim 16, wherein the plurality offiltration sections comprises 2-50 filtration sections, wherein each ofthe plurality of filtration sections has a length of 10 mm-200 mm, awidth of 5 mm-100 mm, and a height of 0.5 mm-2.5 mm.
 19. The hemofilterof claim 16, wherein a curvature of the turnaround sections isnon-uniform, circular, or elliptical or wherein height of the turnaroundsection is non-uniform.
 20. The hemofilter of claim 16, wherein a heightof a filtration section increases from a proximal end, at which bloodenter the filtration section, towards a distal end, at which blood exitsthe filtration section and flows to a turnaround section.